Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Obrowsky, S.
Characterization of intestine-specific lipase-deficient mice
[ Dissertation ] Medical University of Graz; 2012. pp. 116
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- Autor*innen der Med Uni Graz:
- Obrowsky Sascha
- Betreuer*innen:
- Kratky Dagmar
- Levak Sanja
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- Abstract:
- The small intestine is a crucial player in whole body lipid homeostasis due to its ability to regulate energy intake. Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triglyceride (TG) hydrolysis. Deficiency of ATGL results in TG accumulation in multiple tissues, underscoring the critical role of ATGL in maintaining lipid homeostasis. Furthermore, ATGL was shown to produce peroxisome proliferator-activated receptor alpha (PPAR¿) ligands. Herein we elucidated the role of these 2 lipases in the small intestine by generating mice with an intestinal lack of HSL or ATGL, respectively. Intestinal HSL knock out (HSLiKO) mice exhibit increased CE but unchanged TG and diglyceride concentration in the jejunum. Lipid absorption studies revealed that HSLiKO mice have accelerated cholesterol but unchanged TG absorption. Cholesterogenic genes were downregulated in the proximal intestine of HSLiKO mice and consequently less cholesterol biosynthesis was observed. We found decreased TG hydrolase activity and increased intracellular TG content in intestinal ATGL knock out (ATGLiKO) small intestines. Intragastric administration of [³H]trioleate resulted in TG accumulation in the intestine, whereas absorption into the systemic circulation was unchanged. Intraperitoneally injected [³H]oleate accumulated within TG in ATGLiKO intestines, indicating that ATGL mobilizes fatty acids from the systemic circulation absorbed by the basolateral side from the blood. Downregulation of PPAR¿ target genes suggested modulation of cholesterol absorption by intestinal ATGL. Accordingly, we observed delayed cholesterol absorption. In summary we showed that both enzymes play a role in intestinal lipid metabolism. Whereas intestinal HSL deficiency mainly changes cholesterol metabolism by affecting CE concentration and the rate of cholesterol absorption, intestinal ATGL deficiency results in TG accumulation and a downregulation of PPAR¿ target genes and consequently a modulation of fatty acid and cholesterol uptake.